Seasonal influenza is associated with significant mortality worldwide, but pandemic strains that arise unexpectedly from genomic reassortment between influenza strains from diverse species can lead to pandemics and global devastation. While vaccination against influenza is effective, the science of predicting which antigenic epitopes are likely to appear in the next influenza season is an imprecise one and can be further compromised by logistical problems of manufacturing and distribution. Antiviral agents, such as neuraminidase inhibitors (NAIs), are hampered by the increasing resistance of many influenza strains to such agents and the need to be administered very soon after infection. Both of these approaches focus on targeting the virus, rather than the host response to infection. Evidence by Imai et al. (2008) suggested that acute lung injury (ALI) caused by chemical or microbial insults causes oxidative stress that results in generation of an oxidized phospholipid, OxPAPC, a potent agonist of Toll-like Receptor 4 (TLR4)-induced lung inflammation. This observation was extended in the laboratories of the PIs by experiments in which mice with a targeted mutation in TLR4 were shown to be highly refractory to infection with mouse-adapted influenza strain A/PR/8/24 (PR8). The central hypothesis to be tested is that blocking TLR4 signaling therapeutically will protect against influenza infection. We provide compelling evidence in our proposal that the synthetic TLR4 antagonist, Eritoran (E5564), produced by Eisai Inc., and shown to have an excellent safety record in humans through Phase 1-3 clinical trials, blocks influenza infection in mice when administered therapeutically, even later than required for antiviral administration. The proposed plan is a partnership between Eisai Inc. and the University of Maryland, School of Medicine, Sigmovir Biosystems, Inc., and University of Maryland, College of Veterinary Medicine to optimize treatment with Eritoran and NAIs as a therapeutic for influenza infection using mice to optimize treatment regimens and further delineate the effect of influenza infection and Eritoran on the innate immune response, cotton rats to explore efficacy against non-adapted human strains of virus and in a model of aged/immunocompromised animals, and finally, in ferrets, to confirm and extend the use of Eritoran using pandemic strains of influenza under ABSL3 conditions. A Product Development Plan is presented that delineates future plans for moving Eritoran to clinical trial as a therapeutc for influenza.